Reproductive history has a significant impact of development of breast cancer. Nulliparity is an important risk factor for breast cancer, while pregnancy and lactation are associated with reduced risk. Apoptotic cell death of mammary epithelium during postlactational involution may offer an explanation for these differences in risk. Apoptosis is a physiological cell death that eliminates damaged, excess or potentially deleterious cells while maintaining overall tissue integrity. In the course of mammary gland involution, the bulk of secretory epithelium undergoes apoptosis. Thus, during mammary gland involution many of the cells at risk for neoplastic development may be eliminated by apoptotic cell death. Consistent with this hypothesis, experimental studies of liver, B-cell and mammary neoplasias and a recent clinical study of human mammary hyperplasias suggest that failure or inhibition of apoptosis can contribute to tumorigenesis. These observations suggest that not only may failure or misregulation of apoptosis contribute to mammary tumorigenesis but also that regulation of apoptosis may plan an important role in prevention of mammary neoplasia. Thus, understanding the regulation of execution of apoptosis has significant potential for clinical application. The goal of this project is to identify the genes corresponding to putative cell death associated cDNAs isolated from involuting mammary epithelium and determine if they are able to alter the growth of normal, premalignant or malignant mammary epithelial cells. This goal will be accomplished by (1) DNA sequence, Northern blot, immunoblot and immunohistochemical analyses to determine when and where the genes corresponding to clones 4 and 121, lZP and 24p3NGAL are expressed; (2) expressing the genes corresponding to these cDNAs in cell lines derived from normal, premalignant and malignant mammary cells to test their ability to alter growth, (2b) studying the expression of genes that are able to alter growth or induce apoptosis in mammary cells in a collection of mouse mammary tumors that developed spontaneously from premalignant hyperplasias.